title: Intermedin modulates hypoxic pulmonary vascular remodeling by inhibiting pulmonary artery smooth muscle cell proliferation.
abstract: BACKGROUND
  Hypoxic pulmonary arterial hypertension (PAH) is a disabling disease with limited treatment options. Hypoxic pulmonary vascular remodeling is a major cause of hypoxic PAH. Pharmacological agents that can inhibit the remodeling process may have great therapeutic value.
  
  
  OBJECTIVE
  To examine the effect of intermedin (IMD), a new calcitonin gene-related peptide family of peptide, on hypoxic pulmonary vascular remodeling.
  
  
  METHODS
  Rats were exposed to normoxia or hypoxia (∼10% O(2)), or exposed to hypoxia and treated with IMD, administered by an implanted mini-osmotic pump (6.5 μg/rat/day), for 4 weeks. The effects of IMD infusion on the development of hypoxic PAH and right ventricle (RV) hypertrophy, on pulmonary vascular remodeling, on pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis, and on the activations of l-arginine nitric oxide (NO) pathway and endoplasmic reticulum stress apoptotic pathway were examined.
  
  
  RESULTS
  Rats exposed to hypoxia developed PAH and RV hypertrophy. IMD treatment alleviated PAH and prevented RV hypertrophy. IMD inhibited hypoxic pulmonary vascular remodeling as indicated by reduced wall thickness and increased lumen diameter of pulmonary arterioles, and decreased muscularization of distal pulmonary vasculature in hypoxia-exposed rats. IMD treatment inhibited PASMC proliferation and promoted PASMC apoptosis. IMD treatment increased tissue level of constitutive NO synthase activity and tissue NO content in lungs, and enhanced l-arginine uptake into pulmonary vascular tissues. IMD treatment increased cellular levels of glucose-regulated protein (GRP) 78 and GRP94, two major markers of endoplasmic reticulum (ER) stress, and increased caspase-12 expression, the ER stress-specific caspase, in lungs and cultured PASMCs.
  
  
  CONCLUSIONS
  These results demonstrate that IMD treatment attenuates hypoxic pulmonary vascular remodeling, and thereby hypoxic PAH mainly by inhibiting PASMC proliferation. Promotion of PASMC apoptosis may also contribute to the inhibitory effect of IMD. Activations l-arginine-NO pathway and of ER stress-specific apoptosis pathway could be the mechanisms mediating the anti-proliferative and pro-apoptotic effects of IMD.
authors.affiliation: Institute of Hypoxia Medicine, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China.
authors.forename: Sun-Zhong
authors.initials: SZ
authors.lastname: Mao
authors.affiliation: Institute of Hypoxia Medicine, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China.
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Fan
authors.affiliation: Institute of Hypoxia Medicine, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xue
authors.affiliation: Institute of Hypoxia Medicine, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Chen
authors.affiliation: Institute of Hypoxia Medicine, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China.
authors.forename: Xuan-Ying
authors.initials: XY
authors.lastname: Chen
authors.affiliation: Institute of Hypoxia Medicine, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China.
authors.forename: Gong-Sheng
authors.initials: GS
authors.lastname: Yuan
authors.affiliation: Institute of Hypoxia Medicine, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China.
authors.forename: Liang-Gang
authors.initials: LG
authors.lastname: Hu
authors.affiliation: Institute of Hypoxia Medicine, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China; The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA. Electronic address: sliu@lij.edu.
authors.forename: Shu Fang
authors.initials: SF
authors.lastname: Liu
authors.affiliation: Institute of Hypoxia Medicine, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China. Electronic address: fxbwzmc@126.com.
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Gong
mesh_terms: D053607:Adrenomedullin / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D065627:Familial Primary Pulmonary Hypertension; D006360:Heat-Shock Proteins / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000503:physiopathology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D053607:Adrenomedullin; D001120:Arginine; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D009479:Neuropeptides; D009569:Nitric Oxide; C499411:Adm2 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C053387:endoplasmin
keywords: Endoplasmic reticulum stress; Hypoxia; Intermedin; Proliferation; Pulmonary arterial hypertension; l-Arginine–NO pathway